Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MC 903 is a novel vitamin D analogue which has been tested for its effects on cell differentiation and cell proliferation in vitro using the human histiocytic lymphoma cell line U937, and on calcium metabolism in rats in vivo. In the present investigation MC 903 was compared to the natural metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] and to its synthetic analogue 1 alpha-hydroxycholecalciferol [1 alpha (OH)D3]. MC 903 was found to be a potent inducer of cell differentiation and to inhibit cell proliferation and DNA-synthesis in concentrations comparable to those observed with 1,25(OH)2D3. 1 alpha (OH)D3, which is only active after metabolic conversion to 1,25(OH)2D3, was more than 100 times less potent. Oral or intraperitoneal administration of MC 903 to rats showed that the compound was at least 100 times less active than 1,25(OH)2D3 and 1 alpha (OH)D3 in causing hypercalciuria, hypercalcemia and bone calcium mobilisation. The low vitamin D activity of MC 903 was further confirmed by administration of the compound to rachitic rats. The strong direct effects of MC 903 on cell proliferation and cell differentiation, coupled with its decreased activity as a classical vitamin D makes this compound an interesting candidate for studies in human proliferative disorders such as psoriasis.
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PMID:Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. 283 Aug 85

Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.
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PMID:Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria. 755 81

Familial hypocalciuric hypercalcemia (FHH) is generally characterized by lifelong hypercalcemia without hypercalciuria and is inherited in an autosomal dominant manner. Affected individuals show abnormal parathyroid and renal responses to changes in the extracellular calcium concentration. A Japanese FHH family was screened for mutations in the Ca(2+)-sensing receptor gene by the polymerase chain reaction and single strand conformation polymorphism. The proband with hypercalcemia showed an abnormal pattern in exon 1 of the gene, whereas her two sisters with normocalcemia showed a normal pattern. The consanguineous parents with borderline serum calcium concentrations showed both patterns. Nucleotide sequence analysis identified a G-->C point mutation at nucleotide 118 that resulted in the conversion of the normal codon for proline into a codon for alanine at amino acid 40 (numbered according to the bovine complementary DNA). The proband was homozygous for the mutation, and the parents were heterozygous. These results imply that this mutation in the human Ca(2+)-sensing receptor gene causes FHH and that the dosage of the gene defect determines disease phenotype.
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PMID:Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. 767

Dent disease, an X-linked familial renal tubular disorder, is a form of Fanconi syndrome associated with proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, and eventual renal failure. We have previously used positional cloning to identify the 3' part of a novel kidney-specific gene (initially termed hClC-K2, but now referred to as CLCN5), which is deleted in patients from one pedigree segregating Dent disease. Mutations that disrupt this gene have been identified in other patients with this disorder. Here we describe the isolation and characterization of the complete open reading frame of the human CLCN5 gene, which is predicted to encode a protein of 746 amino acids, with significant homology to all known members of the ClC family of voltage-gated chloride channels. CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4. We have shown that the coding region of CLCN5 is organized into 12 exons, spanning 25-30 kb of genomic DNA, and have determined the sequence of each exon-intron boundary. The elucidation of the coding sequence and exon-intron organization of CLCN5 will both expedite the evaluation of structure/function relationships of these ion channels and facilitate the screening of other patients with renal tubular dysfunction for mutations at this locus.
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PMID:Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). 857 51

This study demonstrates that a missense mutation in the voltage gated chloride channel, CLCN5, can cause X-linked renal failure without X-linked recessive hypophosphatemic rickets. A large kindred (Family A), initially evaluated in 1974 with an inherited syndrome characterized by hypercalciuria, nephrocalcinosis, low molecular weight proteinuria, renal tubular acidosis, and renal failure, was clinically re-evaluated and genetically characterized. Medical histories, physical examinations, blood chemistries, and 24-hour urine collections were obtained from 48 family members. Both female and male family members exhibited hypercalciuria, nephrolithiasis, and low molecular weight proteinuria. However, only men developed renal insufficiency, consistent with an X-linked recessive gene defect. Genetic linkage located the disease locus on the proximal short arm of the X chromosome (Xp11) where a voltage gated chloride channel gene, CLCN5, had previously been mapped. DNA sequence of the CLCN5 gene demonstrated a missense mutation (Ser244Leu) in affected family members. The same missense mutation has previously been shown to cause X-linked recessive hypophosphatemic rickets. No affected member of Family A had evidence of chronic hypophosphatemia, clinically significant rickets, or osteomalacia. We hypothesize that genetic background, environment, diet, or an unidentified modifying gene may account for the differing phenotypes resulting from this shared gene defect.
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PMID:CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. 945 24

We report three new Kuwaiti patients with carbonic anhydrase II deficiency (CA II) from two unrelated families. Each patient had osteopetrosis, distal renal tubular acidosis, and cerebral calcification. Patients from family 1 (a brother and a sister) had some facial anomalies and delayed development. At the age of 14 months, ultrasound studies in the girl showed medullary nephrocalcinosis which has not been previously described in association with CA II, while cerebral CT scan revealed dilated ventricles. The patient from family 2, who had two previously reported affected siblings, developed bilateral recurrent renal stones and hypercalciuria but no nephrocalcinosis. None of his affected siblings had nephrocalcinosis or urolithiasis. DNA analysis of patients from both families showed that each of them was homozygous for the "Arabic" mutation in the CA II gene. We report new features in three Arab patients with CAII deficiency. Also review all previously reported CA II cases from Kuwait in order to highlight the inter-/intra-familial variability of the disease in this part of the world despite the overwhelming prevalence of the same "Arabic" mutation among the patient population.
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PMID:Nephrocalcinosis and urolithiasis in carbonic anhydrase II deficiency syndrome. 945 81

Calcium homeostasis by the kidneys and parathyroids is mediated by the calcium-sensing receptor (CaSR), which is located on 3q21-q24 and belongs to family C of the superfamily of G-protein coupled receptors that includes those for metabotropic glutamate, certain pheromones, and gamma-amino butyric acid (GABA-B). Inactivating CaSR mutations result in familial benign hypercalcemia (FBH), or familial hypocalciuric hypercalcemia (FHH), whereas activating mutations result in hypocalcemic hypercalciuria. However, not all FBH patients have CaSR mutations, which, together with the mapping of another FBH locus to 19p13.3, suggests that additional CaSRs or second messengers may be involved. These may be identified by positional cloning, and we therefore performed a genomewide search, using chromosome-specific sets of microsatellite polymorphisms, in an Oklahoma family with an FBH variant (FBHOk), for which linkage to 3q and 19p had been excluded. Linkage was established between FBHOk and eight chromosome 19q13 loci, with the highest LOD score, 6.67 (recombination fraction.00), obtained with D19S606. Recombinants further mapped FBHOk to a <12-cM interval flanked by D19S908 and D19S866. The calmodulin III gene is located within this interval, and DNA sequence analysis of the coding region, the 5' UTR, and part of the promoter region in an individual affected with FBHOk did not detect any abnormalities, thereby indicating that this gene is unlikely to be implicated in the etiology of FBHOk. This mapping of FBHOk to chromosome 19q13 will facilitate the identification of another CaSR or a mediator of calcium homeostasis.
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PMID:Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. 991 58

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. Patients with Dent's disease may also suffer from rickets and other features of the renal Fanconi Syndrome. Patients may have mutations in the X-linked renal chloride channel gene, CLCN5, which encodes a 746-amino-acid protein with 12-13 transmembrane domains. We have investigated the 11 coding exons of CLCN5 for mutations in eight unrelated patients with Dent's disease. Leukocyte DNA was used for the polymerase chain reaction amplification of CLCN5 and the products analyzed for single-stranded conformational polymorphisms (SSCPs). Abnormal SSCPs were sequenced and revealed eight mutations. These consisted of three nonsense mutations (Arg34Stop, Arg648Stop, Arg704Stop), four deletions involving codons 40, 86, 157, and 241, and one acceptor splice consensus sequence mutation tgcag --> tgaag. The mutations were confirmed either by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis. In addition, an analysis of 110 alleles from 74 unrelated normal individuals demonstrated that the DNA sequence changes were not common polymorphisms. All of the mutations predict truncated chloride channels that are likely to result in a functional loss. Thus, our findings expand the spectrum of CLCN5 mutations associated with Dent's disease and the results will help to elucidate further the functional domains of this novel chloride channel.
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PMID:Renal chloride channel, CLCN5, mutations in Dent's disease. 1046 81

We report three boys with adrenal hypoplasia congenita (AHC) and additional findings that represent a new syndrome, IMAGe: Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after birth with growth retardation and severe adrenal insufficiency. Each of the three patients had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all three and epiphyseal dysplasia in two. The patients had documented or suspected hypercalciuria and/or hypercalcemia, resulting in nephrocalcinosis in one and in prenatal liver and spleen calcifications in another. AHC presents most often either as an isolated abnormality, caused by mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome, caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes. All three patients with the IMAGe association had normal creatine kinase levels and no evidence of glycerol kinase deficiency. Sequence analysis of DNA from these patients revealed no mutation in the DAX1- or steroidogenic factor-1-coding sequences, nor was a deletion of DAX1 detected. Identification of the molecular basis of the IMAGe association will give new insight into the pathogenesis of this syndromic relationship involving bone, adrenal cortical, and pituitary development.
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PMID:IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. 1059 84

Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated by a "positional cloning" approach. As a first step in this approach, the chromosomal locations of two disorders referred to as Dent's disease and X-linked recessive nephrolithiasis (XRN) were determined. These two disorders, which represent unusual forms of the renal Fanconi syndrome, are characterized by a low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and renal failure. An X-linked inheritance for XRN was established by studies of a North American kindred, and a similar inheritance for Dent's disease was indicated by the observation of a greater disease severity in males and an absence of male-to-male transmission in five British families. X-linked polymorphic genetic markers were used in linkage studies of these families, and the genes causing Dent's disease and XRN were mapped to Xp11. In addition, in one family with Dent's disease, a microdeletion involving the DNA probe M27 beta was identified. This microdeletion was further characterized by using yeast artificial chromosomes (YACs) and its size was estimated to be 515 Kb. A search for renal-expressed genes from this region identified a novel gene encoding a chloride channel (CLCN5) with similarities to a family of voltage-gated chloride channels. Molecular genetic studies of CLCN5 demonstrated that mutations, which resulted in a functional loss, were associated with Dent's disease and XRN. In addition, such CLCN5 mutations that would result in a functional loss have also been demonstrated in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and an Italian kindred with X-linked recessive hypophosphatemic rickets (XLRH) and hypercalciuria. Thus, four hereditary disorders of nephrolithiasis are due to mutations of the novel chloride channel, CLCN5.
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PMID:Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis. 1072 Sep 30


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